tbuckley/cabot-search huggingface dataset:
Investigation of cardiotoxicity by dipeptidyl-peptidase-4 inhibitors in a human cardiomyocyte cell line as well as in samples from chronic heart failure patients
Authors: I Voros, ZS Onodi, VE Toth, T Gergely, E Saghy, A Gorbe, A Kemeny, P Leszek, ZS Helyes, P Ferdinandy, ZV Varga
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 research and innovation programme, Ministry for Innovation and Technology Background Dipeptidyl-peptidase-4 (DPP4) inhibitors are relatively new therapeutic tools for type 2 diabetes. The SAVOR-TIMI-53 clinical trial has revealed an increased heart failure (HF)-associated hospitalization rate in saxagliptin treated patients. Although this critical side effect could limit the therapeutic use considerably, the mechanism by which DPP4 inhibitors damage the heart is still unclear. Aims We aimed to set up a relevant cellular platform to investigate mechanistically DPP4 inhibition, and the role of its potentially important neuropeptide substrates (e.g. Substance P and Neuropeptide Y). Moreover, we aim to determine the expression of DDP4 and its neuropeptide substrates in human and cellular samples. Methods Western blot, ELISA, and radioimmunoassay experiments were performed to investigate the expression of DPP4 and its neuropeptide substrates in human hearts and in AC16 cells. Viability measurements with calcein staining and scratch assay experiments were used to test the potentially toxic effect of DPP4 inhibitors. The localization of DPP4 mRNA was determined with RNA Scope in situ hybridization. Results Expression of DPP4 and NPY proteins decreased in interventricular septum samples of patients with HF compared to healthy controls. In human hearts DPP4 mRNA is detectable in cardiomyocytes, while other cell types (endothelial cells, fibroblasts, and macrophages) show negligible expression. AC16 human cardiomyocyte cell line expresses DPP4 enzyme. Treatment with various DPP4 inhibitors administered alone or in combination with neuropeptides don’t affect cellular survival; although, in scratch assay experiments treatments with neuropeptides decreased cell migration speed in the isolated neonatal rat cardiomyocyte-fibroblast co-culture. The migration speed reducing effect of NPY was revered by the administration of saxagliptin at the highest concentration of NPY. Conclusions Decreased activity of DPP4 may play a role in the pathomechanism of end-stage congestive heart failure. The DPP4 enzyme could be important as a compensating mechanism against the elevated sympathetic activity in HF and for the altered neuropeptide tone. Inhibition of DPP4 could decrease this adaptive mechanism thereby exacerbating myocardial damage.
Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity
Authors: Ali Aminian, Rickesha Wilson, Abbas Al-Kurd, Chao Tu, Alex Milinovich, Matthew Kroh, Raul J. Rosenthal, Stacy A. Brethauer, Philip R. Schauer, Michael W. Kattan, Justin C. Brown, Nathan A. Berger, Jame Abraham, Steven E. Nissen
Journal: JAMA (2022)

Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk.To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity.In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021.Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265).Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality.The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01).Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.
Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non–Small-Cell Lung Cancer Previously Treated With Immunotherapy—Lung-MAP S1800A
Authors: Karen L. Reckamp, Mary W. Redman, Konstantin H. Dragnev, Katherine Minichiello, Liza C. Villaruz, Bryan Faller, Tareq Al Baghdadi, Susan Hines, Leah Everhart, Louise Highleyman, Vassiliki Papadimitrakopoulou, Joel W. Neal, Saiama N. Waqar, Jyoti D. Patel, Jhanelle E. Gray, David R. Gandara, Karen Kelly, Roy S. Herbst
Journal: Journal of Clinical Oncology (2022)

PURPOSE Resistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.
Peripheral blood T-cell receptor repertoire profiling of advanced non-small cell lung cancer patients receiving PD-1/PD-L1 treatment.
Authors: Diane Tseng, Shin-Heng Chiou, Viswam Nair, Renato G. Martins, Rafael Santana-Davila, Sylvia Lee, Keith D. Eaton, Christina S Baik, A. McGarry Houghton
Journal: Journal of Clinical Oncology (2022)

e21004 Background: Whether peripheral blood T cell receptor (TCR) repertoire profiling can serve as a biomarker to predict clinical benefit from anti-PD-1/PD-L1 checkpoint immunotherapy is not well understood. Moreover, it is not known which methods for TCR repertoire analysis are most clinically meaningful. To address this, we have performed TCR repertoire analysis of patients with advanced/metastatic non-small cell lung cancer (NSCLC) receiving PD-1/PD-L1 treatment. Methods: We analyzed 29 patients receiving PD-1/PD-L1 monotherapy or combination therapy in any line of treatment, excluding patients with EGFR mutations or Alk alterations. Genomic DNA was extracted from peripheral blood examples, and CDR3 regions of the rearranged TCR beta genes were amplified and sequenced using the immunoSEQ platform (Adaptive Biotechnologies, Seattle, WA). Libraries were sequenced using Illumina HiSeq 2500. TCR clonality, diversity, evenness, and the percentage of high-frequency clones (&gt; 0.1% of the repertoire) were calculated at pre-treatment and post-treatment (1 – 3 months) timepoints. Morisita’s overlap index was calculated for 25 paired pre- and post-treatment samples. Metrics were compared in patients with and without durable clinical response at 6 months using the Mann-Whitney test. Results: There were no statistically significant differences in TCR repertoire clonality, diversity, evenness, or high-frequency clones between patients with and without durable clinical benefit, either at pre-treatment or post-treatment time points (p &gt; 0.05). Conclusions: TCR repertoire metrics including clonality, diversity, evenness, percentage of high-frequency clones, and Morisita’s overlap index do not predict immunotherapy responses in this cohort of advanced/metastatic NSCLC patients receiving PD-1/PD-L1 monotherapy or combination therapy. Limitations of this study include sample size and heterogeneity of the patient cohort. This highlights the need for advanced TCR repertoire metrics, for example, considering shared TCR specificities and clonal identity. In ongoing work, we are defining TCR specificity groups and TCR clones in NSCLC as biomarkers of immunotherapy responsiveness.
New diagnostic index for prediction of severe irAEs in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Natalia V. Zhukova, Rashida Orlova, Anna Malkova, Ekaterina Kaledina, Alexandra Demchenkova, Polina Naymushina, V Nazarov, A Mazing, S Lapin, Natalia P. Beliak, Y Shoenfeld
Journal: Journal of Clinical Oncology (2022)

e21565 Background: Immune-related adverse events (irAEs) occur in up to 50% of patients treated with immune checkpoint inhibitors (ICI). Severe forms of toxicity are observed in 3% of patients and require systemic steroid therapy and constant monitoring. One of the considered predictor biomarkers of irAEs development is HLA-genotypes. This research aims to evaluate the diagnostic significance of HLA-DRB1 genotypes and other clinical, laboratory parameters to predict the development of irAEs. Methods: The study involved 28 patients (pts) with metastatic melanoma taking ICI (nivo 53.6%, ipi+nivo 32.1%, other 14.3%). The PD-L1 expression, HLA-DRB1 genotype were evaluated. After 2-3 months the development of irAES was assessed. The complications of 3-4 grade or multi-organ damage were termed as a severe irAEs. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC statistical analysis. The project is supported by a grant (14. W03.31.0009). Results: Different IrAEs developed in 57.1% (16/28) of patients, while severe irAEs in 35.7% (10/28). Among all patients HLA-DRB1 genotypes associated with the risk of autoimmune diseases were found in 78.5% (22/28). The PD-L1 expression was detected in 60.7% (17/28) of individuals.Combination treatment increases the risk of toxicity, p = 0.003, with a diagnostic sensitivity (S) of 56% and a diagnostic specificity (Sp) of 100% (RR = 2.71, OR = 31.67). The analysis of specific complications revealed associations between HLA-DRB1*04 with diabetes mellitus, p = 0.026 (OR = 33.57, S = 100%, Sp = 88.5%), HLA-DRB1*04/15 with autoimmune hepatitis or increased transaminases, p = 0.037 (OR = 17.27, S = 100%, Sp = 72%). An index based on the parameters studied (HLA-DRB1, the absence of PD-L1 expression, type of treatment) was created. With index value ≥2 a sensitivity for predicting severe toxicity is 40.00% and a specificity is 83.33%, p = 0.0126. Conclusions: According to the results obtained it can be assumed that the development of severe forms of irAES has a multifactorial origin, in particular, combination therapy, the absence of PD-L1 expression, which can lead to the loss of ICI drug specificity, and the presence of HLA-DRB1 genotypes associated with the risk of developing autoimmune diseases. The new diagnostic index to predict severe complications based on these parameters was created and showed a sensitivity of 40.00% and a specificity of 83.33%. The authors consider the limitations of the study, such as the small sample, the short observational period.
Contemporary real-world associations between performance status and clinical outcomes in patients with cancer: A retrospective cohort study.
Authors: Deepika Kumar, Elad Neeman, Shiyun Zhu, Hongxin Sun, Dinesh Kotak, Raymond Liu
Journal: Journal of Clinical Oncology (2022)

6578 Background: The ECOG-PS (Eastern Cooperative Oncology Group Performance Status) scale is often used to guide cancer care, but the degree to which it predicts contemporary real-world clinical outcomes, in general and within certain patient groups, is relatively unknown. This retrospective cohort study examined associations between ECOG-PS levels and adverse outcomes in cancer patients with diverse patient characteristics. Methods: Various patient characteristics and nurse-rated ECOG-PS scores (range: 0-4) were recorded for all 21,730 adult patients with cancer receiving intravenous systemic therapy between 01/01/2017 and 12/31/2019 at 18 Kaiser Permanente Northern California cancer centers. Differences in baseline characteristics by ECOG-PS scores were evaluated using chi-square tests for categorical variables and ANOVA for continuous variables. Univariable and multivariable Cox Proportional Hazard models were used to test the ability of ECOG-PS to predict the occurrence of adverse clinical outcomes, including 1-month emergency department (ED) visits and hospitalizations, and 6-month mortality. Results: Overall, 42.5% of patients had ECOG-PS = 0, 42.5% had ECOG-PS = 1, 10.5% had ECOG-PS = 2, 4% had ECOG-PS = 3 and 0.4% had ECOG-PS = 4. Most patients were women (58%), non-Hispanic White (61%), English speakers (93%) and married/domestic partners (63%). African Americans, men, older patients, and those with higher Charlson comorbidity index or Stage IV cancer were found to have higher ECOG-PS levels (all p &lt; 0.001). In multivariable analysis, ECOG-PS of 3-4 were associated with higher ED visits (HR 3.85, 95% CI [3.47-4.26]), hospitalizations (HR 4.7, [4.12-5.36]) and mortality (HR 7.34, [6.64-8.11]), compared with ECOG-PS = 0. Upper gastrointestinal (GI) and Stage IV cancers were associated with a higher risk of ED (upper GI: HR 2.39, [2.12-2.68], (stage IV: HR 1.31, [1.21-1.42]), hospitalization (HR 2.67, [2.27-3.13], (HR 1.51, [1.35-1.68]), and mortality rates (HR 3.37, [2.97-3.81], (HR 1.82, [1.68-1.98]), compared to Breast and Stage I cancers; however, advanced age was not associated with these outcomes. Interactions between ECOG-PS and cancer type as well as ECOG-PS and age group were statistically significant (p &lt; 0.001), such that ECOG-PS was more predictive of adverse outcomes in younger patients and those with breast cancer. Conclusions: In this contemporary real-world cohort, multivariable analysis showed that ECOG-PS, cancer type and stage were strong predictors of ED visits, hospitalizations and mortality; however, advanced age was not. These results also show that ECOG-PS is more predictive of clinical outcomes in certain patient groups. Our findings may have implications on the use of ECOG-PS for clinical decision making.
Propafenone as potential AgoKir: exploration of long-term effects and mechanisms of propafenone on Kir2.1 channel
Authors: E Li, W Kool, L Woolschot, MAG Van Der Heyden
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Chinese Scholarship Council Background Inward rectifying potassium (Kir) channel expression and activity are tightly regulated within the heart. Kir channels play key roles in shaping cardiac action potentials, having a reduced conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. The Kir2.1 channel protein has polyamine binding residues in both the transmembrane (D172) and the cytoplasmic domains (E224,E299), responsible for the process of inward rectification. A reduced functioning of Kir2.1 causes 1) Andersen-Tawil Syndrom and 2) is present in a subset of heart failure patients. Restoration of normal Kir2.1 function by agonists of Kir2.1 (AgoKirs) would be beneficial. The drug propafenone is identified as an AgoKir, but its long-term effects on Kir2.1 protein expression and subcellular localisation is unknown. Purpose To investigate propafenone's long-term effect on Kir2.1 expression and its underlying mechanisms in cell systems. Methods GFP, Dendra2 or non-tagged wildtype (WT) and mutant Kir2.1 expression constructs were transiently or stably (HEK-KWGF; CHO-KD cell lines) expressed in Human Embryonic Kidney and Chinese Hamster Ovary cells. Kir2.1 carried currents were measured by single cell patch clamp electrophysiology. Kir2.1 proteins expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localisation of Kir2.1 proteins. Propafenone was dissolved in DMSO,BaCl2 was used as Kir2.1 channel inhibitor. Results Acute administration of 0.1 and 0.5 µM propafenone increased Kir2.1 carried outward current confirming the drug's Agokir status. Propafenone dose-dependently increased WT Kir2.1 expression levels (2.63±0.40 fold increase at 25 µM and 2.75±0.56 fold increase at 50 µM, 24h) in a process that is independent of the E224, E299 and D172 polyamine binding sites, and the R312 residue which is adjacent to the proposed propafenone binding site. Propafenone (25, 50 µM, 24h) induced intracellular accumulation of WT and mutant Kir2.1 proteins in the late endosome/lysosome compartment (Figure). Channel inhibition by BaCl2 did not affect the propafenone responses on Kir2.1 expression levels or subcellular localisation. Conclusion Acute administration of propafenone at low concentrations increases Kir2.1 currents. Chronic propafenone treatment at only 25-100 times higher concentrations results in increased Kir2.1 protein expression levels and intracellular accumulation in late endosomes and/or lysosomes. Our data support the ability of propafenone at low concentrations to function as AgoKirs without disturbing Kir2.1 protein handing.
The relationship between adherent perinephric fat and the Mayo Adhesive Probability (MAP) score and post-operative functional outcomes in patients subjected to robot-assisted partial nephrectomy
Authors: P. Diana, A. Uleri, G. Lughezzani, E. Beatrici, C. Saitta, N. Frego, M. Paciotti, R. Contieri, M. Lazzeri, A. Saita, R. Hurle, G. Guazzoni, N. Buffi
Journal: European Urology (2022)
The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants
Authors: Marios Koutsakos, Wen Shi Lee, Arnold Reynaldi, Hyon-Xhi Tan, Grace Gare, Paul Kinsella, Kwee Chin Liew, George Taiaroa, Deborah A. Williamson, Helen E. Kent, Eva Stadler, Deborah Cromer, David S. Khoury, Adam K. Wheatley, Jennifer A. Juno, Miles P. Davenport, Stephen J. Kent
Journal: Immunity (2022)
A phase II trial of a chemotherapy-free combination of ponatinib and blinatumomab in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
Authors: Nicholas James Short, Hagop M. Kantarjian, Marina Konopleva, Guillermo Montalban Bravo, Farhad Ravandi, Nitin Jain, Tapan M. Kadia, Yesid Alvarado Valero, Kelly Sharon Chien, Naval Guastad Daver, Walid Macaron, Koji Sasaki, Jennifer Thankachan, Ricardo Delumpa, Ejiroghene Mayor, Wuliamatu Deen, Christopher Loiselle, Monica Kwari, Rebecca Garris, Elias Jabbour
Journal: Journal of Clinical Oncology (2022)

7009 Background: Ponatinib and blinatumomab are highly active in Ph+ ALL. A chemotherapy-free combination of these agents may lead to durable remissions and reduce the need for stem cell transplant (SCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or CML in lymphoid blast phase (CML-LBP) received up to 5 cycles of blinatumomab. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years. All patients (pts) received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2022, 55 pts were treated (35 ND, 14 R/R and 6 CML-LBP). Baseline characteristics and responses are shown in Table. Among 23 pts with ND Ph+ ALL evaluable for response, 22 (96%) achieved CR/CRi; 1 pt had early death due to myelosuppression from prior chemotherapy. Among 13 evaluable pts with R/R Ph+ ALL, 12 (92%) achieved CR/CRi. The CMR rates for the ND, R/R and CML-LBP cohorts were 64%, 71%, and 17% after cycle 1 and were 85%, 79%, and 33% overall, respectively. In the ND cohort, 4/17 evaluable pts (24%) achieved CMR in the peripheral blood within 1 week, and 9/15 (60%) within 2 weeks. The median follow-up is 11 months (range, 1-46+ months). Among the 35 pts in the ND cohort, 33 pts (94%) are alive and in continuous remission. Only 1 pt in the ND underwent SCT in first remission (due to persistent MRD positivity), and no relapses have been observed. The 2-year EFS and OS rates in the ND cohort are 93%. Among the 13 responding pts in the R/R cohort, 6 (46%) underwent SCT. The 2-year EFS and OS rates for the R/R cohort are 42% and 61%, and for the CML-LBP cohort are 33% and 60%, respectively. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to recurrent neurotoxicity. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission. Clinical trial information: NCT03263572. [Table: see text]